title: Synthesis and binding studies of novel diethynyl-pyridine amides with genomic promoter DNA G-quadruplexes.
abstract: Herein, we report the design, synthesis and biophysical evaluation of novel 1,2,3-triazole-linked diethynyl-pyridine amides and trisubstituted diethynyl-pyridine amides as promising G-quadruplex binding ligands. We have used a Cu(I)-catalysed azide-alkyne cycloaddition click reaction to prepare the 1,2,3-triazole-linked diethynyl-pyridine amides. The G-quadruplex DNA binding properties of the ligands have been examined by using a Förster resonance energy transfer (FRET) melting assay and surface plasmon resonance (SPR) experiments. The investigated compounds are conformationally flexible, having free rotation around the triple bond, and exhibit enhanced G-quadruplex binding stabilisation and specificity between intramolecular promoter G-quadruplex DNA motifs compared to the first generation of diaryl-ethynyl amides (J. Am. Chem. Soc. 2008, 130, 15950-15956). The ligands show versatility in molecular recognition and promising G-quadruplex discrimination with 2-50-fold selectivity exhibited between different intramolecular promoter G-quadruplexes. Circular dichroism (CD) spectroscopic analysis suggested that at higher concentration these ligands disrupt the c-kit2 G-quadruplex structure. The studies validate the design concept of the 1,3-diethynyl-pyridine-based scaffold and demonstrate that these ligands exhibit not only significant selectivity over duplex DNA but also variation in G-quadruplex interaction properties based on small chemical changes in the scaffold, leading to unprecedented differential recognition of different DNA G-quadruplex sequences.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. jyotidash@iiserkol.ac.in
authors.forename: Jyotirmayee
authors.initials: J
authors.lastname: Dash
authors.forename: Zoë A E
authors.initials: ZA
authors.lastname: Waller
authors.forename: G Dan
authors.initials: GD
authors.lastname: Pantoş
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
mesh_terms: D000114:Acetylene / Q000138:chemical synthesis / Q000737:chemistry; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D001483:Base Sequence; D002384:Catalysis; D002942:Circular Dichroism; D057930:Click Chemistry / Q000379:methods; D003300:Copper / Q000737:chemistry; D054856:G-Quadruplexes; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D014297:Trimethylsilyl Compounds / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000577:Amides; D008024:Ligands; D011725:Pyridines; D014297:Trimethylsilyl Compounds; D003300:Copper; C023666:pyridine; D000114:Acetylene